Raf-Induced Vascular Endothelial Growth Factor Augments Kaposi's Sarcoma-Associated Herpesvirus Infection

Hamden, Khalief E.; Ford, Patrick W.; Whitman, Audy G.; Dyson, Ossie F.; Cheng, Shi Yuan; McCubrey, James A.; Akula, Shaw M.

doi:10.1128/jvi.78.23.13381-13390.2004

Cited by 22 publications

(28 citation statements)

References 52 publications

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“…1 and 3), indicating that activation of these pathways is We have also shown that activation of MEK pathway alone led to enhanced KSHV infection (Fig. 3B), which was consistent with the results of previous reports (1,26). In contrast, activation of JNK and p38 pathways did not lead to enhanced KSHV infectivity, indicating that activation of these two pathways, though necessary, is not sufficient to promote KSHV infection.…”

Section: Discussionsupporting

confidence: 82%

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Modulation of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by MEK/ERK, JNK, and p38 Multiple Mitogen-Activated Protein Kinase Pathways during Primary Infection

Pan

Xie

et al. 2006

J Virol

113

147

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Infection by viruses alters signaling pathways as a result of cellular response to the infection and virus modulation of its environments. Viruses have evolved to depend on these altered cellular pathways for their successful infection and replication in the host cells. For example, modulation of mitogenactivated protein kinase (MAPK) pathways is essential for infection and replication of human immunodeficiency virus, hepatitis B virus, Epstein-Barr virus, and vaccinia virus (11,23,31,54), while modulation of the NF-B pathway facilitates infection and replication of Epstein-Barr virus, herpes simplex virus type 1, and influenza virus (22, 39, 44).Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is a gammaherpesvirus associated with Kaposi's sarcoma (KS), primary effusion lymphoma, and multicentric Castleman's disease (14). The life cycle of KSHV has two phases. The latent phase, during which the virus is maintained as episomes and has restricted expression of latent genes, is essential for the development of KSHVinduced malignancies (41, 55). The lytic phase, during which the virus produces infectious virions for dissemination, modulates cellular signaling pathways through unrestricted expression of viral genes (14).KSHV infects a variety of cell types, including B cells, epithelial cells, keratinocytes, and endothelial cells. Although KSHV establishes latency in the majority of cell types following primary infection (29), we have found that efficient infection of human umbilical vein endothelial cells (HUVEC) is productive at the early stage of infection, producing large number of infectious virions preceded by strong expression of almost all viral lytic genes (19,53).KSHV entry into the host cells relies on the interaction of its envelope glycoprotein B (gB) with cellular receptor integrin ␣3␤1 (3). This specific ligand-receptor interaction activates focal adhesion kinase and the MEK-ERK1/2 MAPK pathway but not the JNK and p38 MAPK pathways (3, 38). The activation of MEK pathway is important for KSHV infection, since specific inhibitors of MEK pathway reduce KSHV infectivity and the expression of KSHV early transcripts without affecting virus binding (38,42). Consistently, overexpression of Raf, a component of MEK pathway, enhances KSHV infectivity at the postattachment stage (1). Recently, it has been shown that binding of KSHV virions to the cells is sufficient to activate the RTA (Orf50) promoter (32). These studies indicate a role for the MEK MAPK pathway in KSHV infection.We have recently shown that besides the MEK MAPK pathway, KSHV infection also activates JNK and p38 MAPK path-

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Section: Discussionsupporting

confidence: 82%

“…KSHV activates MEK MAPK pathway at the early stage of primary infection, and the MEK pathway, in turn facilitates KSHV infection at the postattachment stage (1,38,50). Specific inhibitors of MEK MAPK pathway reduce KSHV infectivity, whereas constitutive expression of the upstream kinase Raf enhances KSHV infectivity (1,26).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by MEK/ERK, JNK, and p38 Multiple Mitogen-Activated Protein Kinase Pathways during Primary Infection

Pan

Xie

et al. 2006

J Virol

113

147

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“…9,10,16 Briefly, 1 ϫ 10 6 cells were washed twice in RPMI and incubated in phenol red-free RPMI supplemented with 5% FBS at 37°C. After 24 hours incubation (considered as 0 h for experiments in Figure 3A), the target cells were transfected with either ds short interfering RNAs (siRNAs) or the nonspecific (NS) controls using lipofectamine 2000 as per manufacturer's recommendations (Invitrogen).…”

Section: Silencing B-raf and Vegf-a Rna (Sirna)mentioning

confidence: 99%

“…4 In separate studies, we found VEGF-A to enhance KSHV infection of fibroblasts and epithelial cells. 9,10 Interestingly, constitutive activation of the components (Ras/Raf) of the mitogen-activated protein kinase (MAPK) pathway of signaling as well as VEGF expression has been a common feature with KSHV pathogenesis. 11,12 Hence, in this study we attempted to analyze the relationship between the expression of B-Raf and VEGF-A in KSHV-infected hematopoietic cells.…”

Section: Introductionmentioning

confidence: 99%

B-Raf–dependent expression of vascular endothelial growth factor–A in Kaposi sarcoma–associated herpesvirus-infected human B cells

Akula

Ford

Whitman

et al. 2005

Blood

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IntroductionKaposi sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) is the latest addition to the list of human herpesviruses. KSHV was first isolated from Kaposi sarcoma (KS) lesions in persons suffering from acquired immunodeficiency syndrome (AIDS) in 1994. 1 The cancerous conditions that are etiologically associated with KSHV are KS, primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). 2 Apart from the inflammatory cytokines (ICs)/growth factors (GFs), lytic KSHV infection plays an instrumental role in the progression of KS lesions. 3 The lytic cycle of infection is also critical for the spread of KSHV to different organs. Successful KSHV infection is characterized by both virus entry and the ability of the virus to establish latency.In our earlier study, we provided evidence to show that the overexpression of Raf specifically enhanced KSHV infection of target cells at the level of entry. 4 Regulation of Raf is crucial for the proper maintenance of cell growth, proliferation, apoptosis, and differentiation. 5 Of the 3 isoforms, B-Raf has gained a lot of focus over the last couple of years due to the detection of B-Raf somatic missense mutations in malignant melanomas (66%), colon cancers (15%), and at lower frequencies in a wide variety of human cancers. [6][7][8] The ability of Raf to regulate vascular endothelial growth factor-A (VEGF-A) has also been demonstrated. 4 In separate studies, we found VEGF-A to enhance KSHV infection of fibroblasts and epithelial cells. 9,10 Interestingly, constitutive activation of the components (Ras/Raf) of the mitogen-activated protein kinase (MAPK) pathway of signaling as well as VEGF expression has been a common feature with KSHV pathogenesis. 11,12 Hence, in this study we attempted to analyze the relationship between the expression of B-Raf and VEGF-A in KSHV-infected hematopoietic cells. We provide evidences for the existence of a Raf-dependent VEGF-A expression in KSHV-infected hematopoietic cells. Materials and methods Cell cultureHuman foreskin fibroblasts (HFFs; Clonetics, Walkersville, MD), BCBL-1, BC-1 (American Type Culture Collection [ATCC], Manassas, VA; CRL-2230), BC-2 (ATCC CRL-223), BCP-1 (ATCC CRL-2294), and BJAB cells were used in this study. Target cells were grown in either phenol red-free Dulbecco modified Eagle medium (DMEM) or RPMI medium (Invitrogen, Carlsbad, CA) containing 10% charcoal-stripped fetal bovine serum (FBS; Atlanta Biologicals, Lawrenceville, GA), L-glutamine, and antibiotics. 13,14 Dermal microvascular endothelial cells (HMVEC-Ds; CC-2543; Clonetics) were propagated in EGM MV-microvascular endothelial cell medium (Clonetics) as per standard protocols. 13 The passage numbers for HFFs and HMVEC-Ds used in this study ranged between 6 and 10, and 5 and 9, respectively. HFF/pBabePuro3, HFF/⌬B-Raf [DD] :ER, and HFF/⌬B-Raf [FF] : ER cells were cultured as per standard protocols. 4,10 ␤-Estradiol (1 M) stimulation of these cells results in the activation of ⌬B-Raf:ER fusion proteins. 4Inhibitors PD98059 w...

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“…KSHV transformation requires Ras-Raf -dependent signaling (36,37), and paclitaxel is one of the few treatments currently approved for advanced stages of KSHV infection indicates a strong synergistic effect, 0.3 < CI < 0.7 a synergistic effect, 0.7 < CI < 0.9 moderate synergy, 0.9 < CI < 1 additive effect, and CI > 1 antagonistic effect. Concentrations of compounds analyzed were selected based on the discussions in refs.…”

Section: Synergy Of Mcp Compounds With Sorafenib and Paclitaxel In Cementioning

confidence: 99%

In vitro and in vivo synergy of MCP compounds with mitogen-activated protein kinase pathway– and microtubule-targeting inhibitors

Skobeleva

Menon²,

Weber³

et al. 2007

Molecular Cancer Therapeutics

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An important clinical task is to coherently integrate the use of protein-targeted drugs into preexisting therapeutic regimens, with the goal of improving treatment efficacy. Constitutive activation of Ras-dependent signaling is important in many tumors, and agents that inhibit this pathway might be useful in numerous therapeutic combinations. The MCP compounds were identified as inhibitors of Ras-Raf interactions and previously shown to inhibit multiple Ras-dependent transformation phenotypes when used as monoagents in cell culture analyses. In this study, we investigate the ability of the MCP110 compound to synergistically enhance the activity of other therapeutic agents. In both a defined K-Ras -transformed fibroblast model and in human tumor cell lines with mutationally activated Ras, MCP110 selectively synergizes with other agents targeting the mitogen-activated protein kinase pathway, and with multiple agents (paclitaxel, docetaxel, and vincristine) targeting the microtubule network. The synergistic activity of MCP110 and paclitaxel was further established by experiments showing that in Kaposi's sarcoma oncogenically transformed cell lines, cellular models for tumors treated with taxanes in the clinic and in which Raf-dependent signaling plays an important role, MCP110 synergizes with paclitaxel and limit growth. Finally, in vivo testing indicate that MCP110 is bioavailable, inhibits the growth of LXFA 629 lung and SW620 colon carcinoma cells in xenograft models, and again strongly synergizes with paclitaxel. Together, these findings indicate that MCP compounds have potential to be effective in combination with other anticancer agents. [Mol Cancer Ther 2007;6(3):898 -906]

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Raf-Induced Vascular Endothelial Growth Factor Augments Kaposi's Sarcoma-Associated Herpesvirus Infection

Cited by 22 publications

References 52 publications

Modulation of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by MEK/ERK, JNK, and p38 Multiple Mitogen-Activated Protein Kinase Pathways during Primary Infection

Modulation of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by MEK/ERK, JNK, and p38 Multiple Mitogen-Activated Protein Kinase Pathways during Primary Infection

B-Raf–dependent expression of vascular endothelial growth factor–A in Kaposi sarcoma–associated herpesvirus-infected human B cells

In vitro and in vivo synergy of MCP compounds with mitogen-activated protein kinase pathway– and microtubule-targeting inhibitors

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